Process for the production of 3-substituted 7-amino-coumarins

ABSTRACT

Process for the production of 3-substituted 7-amino-coumarins of the general formula IN WHICH X stands for hydrogen or a substituent; n denotes the numbers 1 to 3; and R1 denotes an optionally substituted phenyl or napthyl group, an aromatic-heterocyclic radial which is attached via a C-C bond, on a carboxyl group, characterized in that substituted Beta -phenyl-acrylic acid nitriles of the general formula IN WHICH R1, X and n have the same meaning as above; and R2 stands for a radical WHERE R3 and R4 denote an alkyl radical, for a radical -SO3Z where Z denotes H or a metal atom, or for a radical -CH2OR5where R5 denotes an alkyl, aralkyl, or aryl radical, are heated in an aqueous-acidic medium, optionally in the presence of a water miscible or water-immiscible organic solvent, at temperatures of about 80*-200* C.

United States Patent Knupfer et al.

[ Aug. 1,1972

[54] PROCESS FOR THE PRODUCTION OF S-SUBSTITUTED 7-AMINO- COUMARINS [72]Inventors: Hans Knupfer, Berg. Neukirchen; Carl-Wolfgang Schellhammer,Opladen, both of Germany [73] Assignee: Farbenfabriken BayerAktiengesellschaft, Leverkusen, Germany [22] Filed: Aug. 21, 1969 [21]Appl. No.: 852,105

[30] Foreign Application Priority Data Aug. 23, 1968 Germany ..P 17 93262.6

[52] U.S. Cl...260/343.2 R, 260/332.2 H, 260/296 B, 260/309.2, 260/465E, 260/296 R, 260/332.3

[51 1 Int. Cl. ..C07d 7/24 [58] Field of Scarch.....260/332.2 H, 343.2R, 296 B, 260/309.2

[56] References Cited UNITED STATES PATENTS 3,514,47l 5/1971Yanagisawaetal. ..260/343.2

Primary Examiner-John M. Ford All0rneyPlumley & Tyner 5 7 ABSTRACTProcess for the production of 3-substituted 7-aminocoumarins of thegeneral formula 0 HQN O in which R X and n have the same meaning asabove; and R stands for a radical where R and R denote an alkyl radical,for a radical SO;,Z where Z denotes H or a metal atom, or for a radicalCl-l OR where R denotes an alkyl, aralkyl, or aryl radical, are heatedin an aqueous-acidic medium, optionally in the presence of a watermiscible or water-rmmisci le organic solvent, at temperatures of about80-200 C.

5 Claims, N0 Drawings PRGCESS FOR PRODUCTION OF 3- The present inventionrelates to a process for the production of 3-substituted7-amino-coumarins of the general formula CN CH=CR1 HzN in which R,, Xand n have the same meaning as above; R stands for a radical where R andR, denote an alkyl radical, or for a radical SO Z where 2 denotes H or ametal atom, preferably an alkali metal atom such as Na or K, or for aradical CH OR where R denotes an alkyl, aralkyl or aryl radical, areheated in an aqueous-acidic medium, optionally in the presence of anorganic solvent which may or may not be miscible with water, attemperatures of about 80200 C, preferably at temperatures of 100 1 50 C.

When the process is carried out according to the invention, hydrolysisof the nitrile group, elimination of the protective group R and closureof the coumarin ring take place in one operation. The reaction productsare isolated in the usual way, for example, by cooling and filtering offwith suction.

In general, the process according to the invention is carried out byheating 1 mol of the substituted ,8phenyl-acrylic acid nitrile of theformula (II) in an aqueous medium, optionally under pressure, in thepresence of at least 2 mol of a mineral acid, for example, sulphuricacid, hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloricacid or phosphoric acid, optionally in the presence of a water-miscibleorganic solvent, e.g., acetic acid, or a water-immiscible solvent, e.g.,chlorobenzene or o-dichlorobenzene, at 80200 C, preferably lOO-l50 C,for about 1 to 20 hours, and subsequently isolating the reaction productin the usual way.

Suitable radicals R, are, for example, phenyl or naphthyl radicals whichmay be substituted by alkyl, alkoxy or halogen, as well as optionallysubstituted thienyl, pyridyl, or benzimidazolyl radicals. Suitablestarting compounds are, for example, those set out in the followingTable (the numbers in brackets refer to the position of thesubstituent).

The compounds of the formula (II) can be obtained, for example, by firsttreating toluene derivatives of the general formula O- N OR2 in which X,n and R have the same meaning as above, in an aqueous-alkaline medium,preferably in the presence of organic solvents, at temperatures of about50 to 120 C with an alkali metal polysulphide, and subsequently reactingthe product, without intermediate isolation, preferably at temperaturesof to 120 C, with nitriles of the formula R Cl-h-CN (IV) in which Rdenotes an optionally substituted phenyl or naphthyl group, anaromatic-heterocyclic radical which is linked to the group CH via acarbon atom, a carboxyl, carboxamide or carboxylic ester group, andsubsequently isolating the reaction products in the usual way, forexample, by cooling, possibly acidification, and filtering off withsuction. The carboxamide and carboxylic ester groups are thus convertedinto carboxylic acid groups.

The process described above is usually carried out by mixing a solutionof the toluene derivative (Ill) at temperatures of about 50 to 120 C inan organic watermiscible solvent, for example, an alcohol or dirnethylsulphoxide, with at least the amount of an aqueous-alkaline polysulphidesolution required for reduction of the nitro group or oxidation of themethyl group, heating at 50 to 120 C for about & to 3 hours,subsequently adding, possibly after cooling, about 0.7 to 1 mol of thenitrile (iV), heating for a prolonged time, if desired, and subsequentlyisolating the reaction product in the usual way.

Suitable toluene derivatives of the formula (iii) are,

for example: N,N-dimethyI-sulphamic acid-(Z-methyl-S-nitro-phenyl)ester, (2-N,N-dimethyl-sulphamidoxy-4-nitrotoluene), N,N-dimethyl-sulphamic acid-(2,4-dimethyl- S-nitro-phenyl) ester, theNaor K-salt of sulphuric acid-(Z-methyl-S-nitro-phenyl) semiesters,Z-(methoxy-methoxy)-4-nitro-toluene.

Suitable nitn'les of the general formula (IV) are, for example:phenyl-acetonitrile, p-tolyl acetonitrile, mtolyl-acetonitrile,(3,S-dimethyl-phenyl)-acetonitrile, (4-chloro-phenyl)-acetonitrile,(3,4-dichlorophenyl)- acetonitrile,(4-methyl-sulphonylphenyl)-acetonitri1e,

(4-methoxy-phenyl)-acetonitrile, naphthyl-1- acetonitrile,naphthyLZ-acetonitrile, thienyl-Z- acetonitrile,pyridine-Z-acetonitrile, pyridine-3- acetonitrile,pyridine-4-acetonitrile, cyanoacetic acid and cyanoacetic acid ethylester.

Suitable solvents for the preparation of the aqueousorganic medium areprimarily lower alcohols, for example, methanol, ethanol and propanol,and also dimethyl sulphoxide.

The term alkali metal polysulphides refers to polysulphides which can beobtained by dissolving sulphur in an aqueous alkali metal hydroxideand/or alkali metal sulphide, the preferred alkali metal compounds beingthe sodium or potassium compounds.

It was already known from Swiss Pat. specification No. 341,834, toconvert a-aryl-B-(2-alkoxy-4- acylamino)-acrylo-nitriles in a two-stepreaction into the corresponding 3-substituted 7-amino-c0umarins; in thisprocess, strong acids in an anhydrous medium were used as condensationor splitting agent, and after condensation the acylamino group washydrolyzed to form the free amino group. It was therefore new andcompletely surprising that 3-substituted 7-amino-coumarins can beobtained in a simple manner with high yields and high degrees of purityin a single-step process by condensation in an aqueous medium.

The amino-coumarins of the formula (I) which can be obtained accordingto the invention are known. They are optical brighteners or valuableintermediates for the production of optical brighteners which areobtained, for example, by alkylation or acylation of the amino-group inthe 7-position. The preparation of such brighteners is described, forexample, in US. Pat. Nos. 2,881,286; 2,929,822; 2,945,033; 2,242,177;and in Belgian Pat. Specification No. 660,602.

Example 1 155 Parts a-phenyl-[H2-N,N-dimethylsulphamidoxy-4-amino-phenyl)-acrylonitrile are heated in amixture of 450 parts of water and 830 parts of concentrated sulphuricacid at 130 C for 7 hours while stirring. After cooling to about 20 C,the product is filtered off with suction and washed with l-2 percentsulphuric acid. The filter cake is suspended in 500 parts of water andthe suspension adjusted to pH 8-9 with concentrated aqueous ammonia.After filtering off with suction, washing with water and drying, thereare obtained parts 7-amino-3-phenyl-coumarin coumarin of m.p. 209-2 10C.

If thea-phenyl-B-(2-N,N-dimethyl-sulphamidoxylamino-phenyl)-acrylonitrile isreplaced with corresponding amounts of the following substitutedacrylonitriles, then the substituted coumarins indicated below areobtained in similar yields: a-(p-tolyl)-B-(2N,N-dimethyl-sulphamidoxy-4-amino-phenyl acrylonitrile yields3-p-tolyl-7-amino-coumarin of m.p. 225-226 C;

a-(4chlorophenyl)-B-(2-N,N-dimethylsulphamidoxy-4-amino-phenyl)-acrylonitrile yields 3-(4-chlorophenyl)-7-amino-coumarin of mp. 26 7269 C;

a-( 3 ,4-dichlorophenyl )-B-(2-N,N-dimethylsulphamidoxyl-amino-phenyl)-acrylonitrile yields 3-(3,4-dichlorophenyl)-7-amino-coumarin of m.p. 225256 C;

a-phenyl-/3-( Z-hydrogensulphato-4amino-phenyl acrylonitrile yields3-phenyl-7-amino-coumarin of m.p. 208-210 C.

Example 2 15 Parts a-( 4-methoxy-phenyl)-B-(2-N,N-dimethylsulphamidoxy-4-amino-phenyl)-acrylonitrile are suspendedin 60 parts of water, and 3 1.5 parts of glacial acetic acid and 83parts of concentrated sulphuric acid are then added. The mixture isstirred at 114-116 C for 8 hours, allowed to cool, the product isfiltered off with suction and washed with 1-2 percent sulphuric acid.The filter cake is suspended in 50 parts of water and the suspensionadjusted to pH 8-9 with a concentrated ammonia solution. After filteringofi with suction, washing with water and drying, there are obtained 10parts B-(p-rnethoxy-phenyl)-7-amino-coumarin of m.p. 252-253 C.

If. the a-(4-methoxy-phenyl)-B-(2-N,N-dimethylsulphamidoxy-4-amino-phenyl)-acrylonitrile is replaced withcorresponding amounts of the following substituted acrylonitriles, thenthe coumarins indicated below are obtained in similar yields:

a-( naphthyl- 1 )-B-( 2-N,N-dimethyl-sulphamidoxy-4-amino-phenyD-acrylonitrile yields 3-(naphthyl-l)-7- amino-coumarin ofm.p. 247248 C;

a-(naphthyl-Z )-B-(2-N,N-dimethyl-sulphamidoxy-4-amino-phenyD-acrylonitrile yields 3-(naphthyl-2)-7- amino-coumarin ofm.p. 239-24l C;

a-(phenyl)-B-(2-N,N-dimethyl-sulphamidoxy-4-amino-S-methyl-phenyl)-acrylonitrile yields 3-phenyl-6-methyl-7-amino-coumarin of m.p. 2 l 9-220 C;

a-(benzimidazolyl-Z)-B-(2-N,N-dirnethylsulphamidoxy-4-amino-phenyl)-acrylonitrile yields 3-(benzimidazolyl-2)-7-amino-coumarin of m.p. 34234 3 C;

a-phenyl-B-(Z-(methoxy-methoxy)-4-amino-phenyl)-acrylonitrile yields3-phenyl-7-amino-coumarin of m.p. 208-2 10 C.

Example 3 22.5 Partsa-(thienyl-2)-}3-(2-N,N-dimethylsulphamidoxy-4-aminophenyl)-acrylonitrile are heated in a mixture of 100 parts of water, 105parts of glacial acetic acid and 135 parts of concentrated sulphuricacid at l04l06 C for 6 hours. After cooling, the product is filtered ofiwith suction, washed with 1 2 percent sulphuric acid, the filter cake issuspended in 100 parts of water and the suspension adjusted to pH 8-9with a concentrated ammonia solution. 12.6 Parts3-(thienyl-2)-7-amino-coumarin of m.p. 23 1-234 C are thus obtained.After recrystallization from chlorobenzene, the red-yellow crystalneedles melt at 236-237 C.

Example 4 C.

48 Partsa-(p-tolyl)-B-(2-N,N-dimethylsulphamidoxy-4-amino-phenyl)-acrylonitrileare heated in a mixture of 190 parts of water, 275 parts of concentratedsulphuric acid and 65 parts dichlorobenzene at 120-l30 C for 10 hours.After cooling, the product is filtered off with suction and the residuesuspended in 200 parts of water is adjusted to pH 8-9 with aconcentrated ammonia solution. 30 Parts 3-(p-tolyl)-7-amino-coumarin ofm.p. 225226 C. are obtained.

Example C The starting compounds used in the Examples l-4 can beobtained as follows:

a. A solution of 24 parts Na S 9 H 0, 19 parts NaOH and parts of sulphurin 100 parts of water is added dropwise at boiling temperature to asolution of 54.5 parts (2-methyl-5-nitro-phenoxy)-dimethyl ether(prepared from 2-hydroxy-4-nitro-toluene and chlorodimethyl ether) in158 parts ethanol and 100 parts of water. The mixture is boiled for l rhours, 28 parts benzyl cyanide are added, boiling is continued for 60minutes and the mixture is allowed to cool to 20 C. After filtering offwith suction and washing with 50 percent ethanol, there are obtained 21parts a-phenyl-/3-[ 2-(methoxy-methoxy)-4-amino-phenyl]-acrylonitrile ofm.p. 85.5 to 86 C.

b. A solution of 13.2 parts Na s 3 H 0, 19 parts NaOH and 10 parts ofsulphur in 100 parts of water is added dropwise within 10 to 20 minutesto a boiling solution of 72 parts N,N-dimethyl-sulphamic acid-( 2-methyl-S-nitro-phenyl) ester (prepared from 2-hydroxy-4-nitro-tolueneand N,N-dimethyl-sulpharnic acid chloride) in 158 parts ethanol and 100parts of water. The mixture is boiled for 1% hours, 28 parts benzylcyanide are then added, and boiling is continued for 30 minutes. Themixture is then cooled to 40 C. After filtering off with suction andwashing with 50 percent ethanol, there are obtained 59.5 partsa-phenyl-B-( 2- N,N-dirnethyl-sulphamidoxy-4-amino-phenyl)-acrylonitrile of m.p. 153-154 C.

If the benzyl cyanide is replaced with corresponding amounts of thefollowing substituted acetonitriles, then the acrylonitriles indicatedbelow are obtained in similar yields:

p-tolyl-acetonitrile yields a(p-tolyl)-B-(2-N,N-dimethyl-sulphamidoxy-4-amino-phenyl)-acrylonitri1e of m.p. 18ll82 C;4-methoxybenzyl cyanide yieldsa-(4-methoxyphenyl)-B-(2-N,N-dimethylsulphamidoxy-4-amino-phenyl)-acrylonitrileof m.p. 169l 7 1 C;

4-chlorobenzyl cyanide yields a-(4-ch1orophenyl)-B-(2-N,N-dimethyl-sulphamidoxy-4-amino-phenyl)- acrylonitrile of m.p.198-l 99 C;

3,4-dichlorobenzyl cyanide yieldsa-(3,4-dichlorophenyl)-B-(2-N,N-dimethyl-sulphamidoxy-4-aminophenyl)-acrylonitrileof m.p. l196 C;

naphthyll-acetonitrile yields a-(naphthyl-l )-B-( 2-N,N-dimethyl-sulphamidoxy-4-aminophenyl)- acrylonitrile of m.p. l54l56C; naphthyl-2- acetonitrile yields a-(naphthyl-2)-,B-(2-N,N-dimethylsulpharnidoxy-4-aminophenyl)-acrylonitrile of m.p. l90-l92 C;thienyl-2-acetonitrile yields a-(thienyl-2)-/3-(2-N,N-dimethyl-sulphamidoxy-4-aminophenyl)- acrylonitrile of m.p.207-208 C; pyridine-2- acetonitrile yieldsa-(pyridyl-2)-B-(2-N,N-dimethylsulphamidoxy-4-aminophenyl)-acrylonitrileof m.p. 168-l 69 C.

c. A solution of 72 parts N,N-dimethyl-sulpha.micacid-(2-methyl-5-nitro-phenyl) ester in 158 parts ethanol and parts ofwater is mixed at boiling temperature with a solution of 24 parts Na s 9H 0, 19 parts NaOH and 10 parts of sulphur in 100 parts of water. Themixture is boiled for 1% hours, 26 parts cyanoacetic acid ethyl esterare added, and boiling is continued for 30 minutes. After cooling, thepH is adjusted to 5 to 6 with acetic acid. After filtering off withsuction, there are obtained 35 parts a-carbohydroxy-B-(2-N,N-dimethyl-sulphamidoxy-4-aminopheny1)- acrylonitrile of m.p. 234to 235 C (decomp).

d. A solution of 38 parts benzimidazolyl-Z- acetonitrile in 100 parts ofa 10 percent sodium hydroxide solution is added at boiling temperatureto a solution of 2-N,N-dimethyl-sulphamidoxy-4-arninobenzaldehydeprepared as in Example 4, the mixture is boiled for 1 hour, and CO isintroduced at boiling tem- In 1047 nms perature until the precipitationis complete. After cooling and filtering ofi with suction, there areobtained 45 partsa-(benzimidazolyl-2)-B-(2-N,N-dimethylsulphamidoxy-4-amino-phenyl)-acrylonitrileof m.p. 231 to 233 C.

e. A solution of 24 parts Na S 9 H 0, 27 parts NaOH and parts of sulphurin 100 parts of water is added dropwise to a boiling solution of 76parts 2-N,N- dimethyl-sulphamidoxy-4-nitrol ,S-dirnethyl-benzene in 158parts ethanol and 100 parts of water. The mixture is boiled for 1%hours, 28 parts benzyl cyanide are then added, and boiling is continuedfor hour. After cooling'to 30 C and filtering off with suction, thereare obtained 34.5 parts a-phenyl-B-(2-N,N-dimethylsulphamidoxy-4-amino-5-methyl-phenyl)-acrylonitrile ofm.p. 143 to 144 C.

f. A solution of 24 parts Na S 9 H 0, 19 parts NaOl-l and 10 parts ofsulphur in 100 parts of water is poured within to minutes into a boilingsolution of 70.5 parts of the sodium salt of sulphuric acid-(2-methyl-5- nitro-phenyl) semiester in 158 parts ethanol and 100 partsof water. The mixture is boiled for 1% hours, 28 parts benzyl cyanideare added, and boiling is continued for a further hour. After cooling,the mixture is acidified with a dilute sulphuric acid. The residue isdissolved in a 10 percent sodium carbonate solution and afterclarification with active charcoal, the solution is reacidified withdilute sulphuric acid. There are thus obtained parts of a yellownon-melting product which according to spectral findings has thestructure of a-phenyl-B-( 2-hydrogensulphato-4-amino-phenyl)-acrylonitrile.

We claim:

1. Process for the production of 3-substituted 7- amin0-coumarin offormula in which X is hydrogen or methyl;

n is 1, 2 or 3;

R, is a radical attached via a C-C bond selected from the groupconsisting of phenyl; naphthyl; phenyl or naphthyl substituted withlower alkyl, lower alkoxy or halogen; benzimidazolyl; thienyl; pyridyl;and carboxyl;

X is hydrogen or methyl;

by heating a B-phenyl-acrylic acid nitrile of the formula in which R Xand n have the same meaning as above;

& and R, are lower alkyl, or taken together, form the divalent radical(CH Z is hydrogen or a metal atom; and

R is methyl; in an aqueous-acidic medium at temperatures of about 2 0 0C.

2. The process of claim 1 in which said reaction medium contains, inaddition, a water-miscible organic solvent. I

3. The process of claim 1 in which said reaction medium contains, inaddition, a water-immiscible organic solvent.

4. The process of claim 1 in which the reaction is carried out in anaqueous-acidic medium which contains mineral acid in a molar ratio of atleast 2: 1 based on the nitrile.

5. The process of claim 1 which is conducted at a temperature of -150 C.

2. The process of claim 1 in which said reaction medium contains, inaddition, a water-miscible organic solvent.
 3. The process of claim 1 inwhich said reaction medium contains, in addition, a water-immiscibleorganic solvent.
 4. The process of claim 1 in which the reaction iscarried out in an aqueous-acidic medium which contains mineral acid in amolar ratio of at least 2:1 based on the nitrile.
 5. The process ofclaim 1 which is conducted at a temperature of 100*-150* C.